Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic Escherichia coli Infection.

Haiyan Ren,Ganwu Li,Xuhua Chen,Fengwei Jiang

doi:10.3389/fmicb.2020.00708

Abstract

Extraintestinal pathogenic Escherichia coli (ExPEC) is one of the top pathogens responsible for bloodstream infection and severe, often fatal, sepsis. Although the virulence factors and host immune responses to ExPEC infection have been investigated, the responses to a particular ExPEC strain could be very different. In this study, we investigated the mechanisms of Cyclooxygenase-2 (COX-2) up-regulation in influencing the host defenses against infection of ExPEC XM O2:K1:H7. Our results demonstrated that ExPEC XM O2:K1:H7 infection in mouse and RAW264.7 macrophages leads to COX-2 up-regulation, and COX-2 inhibition significantly enhances ExPEC infection. The up-regulation of COX-2 in macrophages was mediated by Toll-like receptor 4 (TLR4) through the activation of p38 and extracellular signal-regulated kinase/Mitogen-activated protein kinase (ERK/MAPK) pathways. Further studies showed that COX-2 inhibition significantly decreased autophagy in macrophages during ExPEC XM O2:K1:H7 infection. Autophagy inhibition significantly enhanced, while induction reduced ExPEC XM O2:K1:H7 survival in macrophages. In addition, COX-2 inhibition significantly increased macrophage cell death during ExPEC XM O2:K1:H7 infection and increased the expression of anti-inflammatory cytokine interleukin-10 (IL-10). Our results indicate that COX-2 up-regulation benefits host defense against ExPEC XM O2:K1:H7 infection by increasing autophagy in macrophages and by reducing IL-10 expression and macrophage cell death during ExPEC infection.

Highlights

Extraintestinal pathogenic E. coli (ExPEC) are the major gram-negative pathogens responsible for a spectrum of diseases in humans and animals, including septicemia, neonatal meningitis, and urinary tract infections
The mRNA level of COX-2 was confirmed to be upregulated at 6 hpi and 12 hpi in the ExPEC XM O2:K1:H7infected spleen using quantitative real-time reverse transcription PCR (Figure 1A)
To further explore the function of COX-2 in ExPEC XM O2:K1:H7 infection, bacterial loads of ExPEC XM O2:K1:H7 in BALB/c mice treated with NS398, a specific COX-2 inhibitor, or DMSO vehicle were assessed

Summary

Introduction

Extraintestinal pathogenic E. coli (ExPEC) are the major gram-negative pathogens responsible for a spectrum of diseases in humans and animals, including septicemia, neonatal meningitis, and urinary tract infections. ExPEC are responsible for 70–95% of urinary tract infections and 20–40% of neonatal meningitis (Russo and Johnson, 2003; George and Manges, 2010). COX-2 Up-Regulation Against ExPEC Infection caused by ExPEC infection in humans can develop into septicemia, which is the major cause of mortality (Kirkby et al, 2012; Poolman and Wacker, 2016). Conservative estimates show that E. coli is responsible for 17% of cases of severe sepsis (Russo and Johnson, 2003). The emergence of multidrug resistance in ExPEC underscores the urgent need to develop alternative treatments to manage the systemic infection caused by ExPEC (Alhashash et al, 2013)

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Results

Conclusion